Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; State Key Laboratories for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China; Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China.
State Key Laboratories for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.
Phytomedicine. 2019 Feb;53:243-251. doi: 10.1016/j.phymed.2018.09.019. Epub 2018 Sep 5.
Astragalosidic acid (LS-102) is a new water-soluble derivative of astragaloside IV - a major effective component isolated from the Chinese herb Astragali Radix. Our previous study showed that LS-102 exhibited potent cardiovascular activity.
The objective of this study was to investigate the pharmacokinetic properties of LS-102 after single-dose, oral administration in beagle dogs by developing and validating an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method.
The chromatographic separation was performed on a Acquity HSS C column (100 mm × 2.1 mm, 1.8 µm) by a gradient elution using a mobile phase consisting of water and acetonitrile at a flow rate of 0.35 ml/min. The analytes were detected with a triple quadrupole tandem mass spectrometry in multiple reaction monitoring mode. Method validation revealed a wide linearity over the range of 2.0-10,000 ng/ml together with satisfactory intra- and inter-day precision, accuracy, and recovery. Stability testing showed that LS-102 spiked into dog plasma was stable for 4 h at room temperature, for up to 2 weeks at -80 °C, and during three freeze-thaw cycles. The method was effectively and successfully applied to the pharmacokinetics of LS-102 after oral administration (5, 10 and 20 mg/kg) to beagle dogs. Peak plasma concentrations are attained within approximately 2 h after oral administration with a half-life ranging from 1.55 h to 4.49 h. The plasma concentration-time curve of LS-102 after oral administration presents the phenomenon of a double-peak absorption phase. The peak concentration and area under the concentration-time curve of LS-102 seemed to increase with the increasing doses proportionally, that suggesting linear pharmacokinetics in dogs. Meanwhile, the doxorubicin (Dox)-injured H9c2 cell model was prepared by incubating the cells in 1 µM Dox for 24 h. MTT assay and LDH release measurement showed that LS-102 protected against Dox-induced cardiomyocyte death.
The obtained results may help to guide the further pre-clinical research of LS-102 as a potentially novel cardioprotective agent.
黄芪甲苷（LS-102）是黄芪的主要有效成分黄芪甲苷的一种新型水溶性衍生物。我们之前的研究表明 LS-102 具有很强的心血管活性。
本研究旨在通过建立和验证超高效液相色谱-串联质谱（UPLC-MS/MS）法，研究犬单次口服 LS-102 后的药代动力学特性。
色谱分离在 Acquity HSS C 柱（100mm×2.1mm，1.8μm）上进行，采用水和乙腈为流动相的梯度洗脱，流速为 0.35ml/min。分析物采用三重四极杆串联质谱在多重反应监测模式下检测。方法学验证表明，该方法在 2.0-10000ng/ml 范围内具有良好的线性关系，且日内和日间精密度、准确度和回收率均令人满意。稳定性试验表明，LS-102 加入犬血浆后在室温下 4h、-80°C 下长达 2 周以及 3 次冻融循环中均稳定。该方法有效地应用于犬口服（5、10 和 20mg/kg）LS-102 的药代动力学研究。口服后约 2h 达到峰血浆浓度，半衰期为 1.55-4.49h。LS-102 口服后的血药浓度-时间曲线呈现双峰吸收相现象。LS-102 的峰浓度和药时曲线下面积似乎随剂量呈比例增加，提示犬体内呈线性药代动力学。同时，通过孵育细胞 24h 于 1µM Dox 制备阿霉素（Dox）损伤的 H9c2 细胞模型。MTT 测定和 LDH 释放测定表明 LS-102 可防止 Dox 诱导的心肌细胞死亡。
所得结果可能有助于指导 LS-102 作为潜在新型心脏保护剂的进一步临床前研究。
